Our goal is to elucidate the mechanisms by which ethanol, diphenylhydantoin, oral contraceptives, and other drugs impair folate metabolism. We have shown that ethanol acutely lowers the serum folate level in subjects fasting or eating folate-deficient diets. We will study the effect of ethanol on serum and urine folate level in subjects eating various normal diets. We find that oral contraceptives do not seem to cause folate deficiency anemia in otherwise normal women. We will determine if oral contraceptives increase urinary folate loss. We studied the effect of serum folic acid binding protein (FABP) on radioassays for serum folate and we are investigating the physiologic significance of FABP in man. Elevations of FABP decrease the whole serum radioassay value, but do not affect the heat-extracted value. We found an inverse relationship between the level of FABP and the level of serum L. casei folate in patients taking large doses of folic acid, but a direct relationship in a normal subject on a constant diet and in patients with uremia. Aspirin, a drug known to displace some agents from serum binders, caused a 15-20% fall in mean daily serum folate level in a normal subject. In vitro experiments suggested that aspirin may modify serum binding of tritiated folic acid. Our data suggests that the elevated FABP in uremia apparently does not retard delivery of folate to the marrow in vivo. We plan to study the effect of intravenous and oral diphenylhydantoin on serum and urine folate level, and to continue our studies of the role of folate binders in human folate metabolism.